Sudden cardiac death (SCD) claims the lives of approximately 350,000 Americans each year. Emerging evidence indicates an important role for genetic predisposition to SCD; however, the molecular determinants have remained elusive. The overall goal of this proposal is to investigate new mechanisms that underlie SCD through the application of innovative technology and the novel use of new genetic models of long QT syndrome 1 (LQT1). This multi-pronged approach includes the investigation of LQT1 rabbits with myocardial damage/cardiomyopathy induced by either tachypacing (TICM) or coronary embolization (MI). The proposal is composed of three Specific Aims: 1) To create and characterize a model of myocardial infarction (MI) and a model of tachycardia induced cardiomyopathy (TICM) in male littermate controls (LMC) and LQT1 rabbits and to characterize of the incidence of spontaneous ventricular arrhythmias and sudden cardiac death with the use of telemetric ECG monitoring and in vivo invasive electrophysiological studies. 2) To elucidate the contribution of IKs down-regulation to triggers and substrate of arrhythmias by analyses (ex vivo) of spontaneous arrhythmias, action potential duration, dispersion of repolarization, conduction, triggered activity and the heterogeneities in electrical/mechanical restitution, and conduction block using surface optical mapping of action potential and calcium transients and fiberoptic fibers-mediated in depth optical mapping of rabbit heart preparation of these models. 3) a. To perform a comparative analysis of action potential and calcium-handling properties in myocytes isolated from the LV of TICM and MI LQT1 and LMC rabbits under control conditions and during autonomic receptor stimulation, using patch-clamp and fluorescent-indicator techniques; b. To use cellular electrophysiology, histochemistry, protein expression studies, quantitative real-time PCR to elucidate the cellular and molecular basis of the arrhythmias observed in Aims 1&2 by comparing the molecular determinants of the differences in cardiac repolarization, conduction, and calcium-handling proteins expressed in models of MI and TICM induced in LMC and LQT1 rabbits. PUBLIC HEALTH RELEVANCE: Public Health Relevance The characterization of transgenic rabbit models for cardiac arrhythmias, the effects of myocardial dysfunction, and the identification of the relationship between mutant LQTS genes that encode for dysfunctional ion channels and life-threatening ventricular tachyarrhythmias should provide more complete knowledge into the genetic and electrophysiologic factors involved in repolarization disorders. These studies into altered ventricular repolarization should contribute important new insights into sudden cardiac death mechanisms associated with acquired cardiac disorders that accompany ischemic and nonischemic cardiomyopathy and QT- prolonging drugs. This enhanced knowledge should lead to more effective strategies for prevention of sudden death in a broad spectrum of genetic and acquired cardiac disorders with meaningful public health benefits.